The cAMP signal transducing system comprises a number of proteins embedded in the plasma membrane, including an adenylyl cyclase catalyst, cell-surface receptors, and a pair of homologous guanine nucleotide binding (so-called "G") proteins (Levine, 1991, N. Engl. J. Med. 325: 1738-1740; Gilman, 1987, Ann. Rev. Biochem. 56: 615-649). One of the G proteins, termed G.sub.s, couples stimulatory receptors to the activation of adenylyl cyclase (Levine, 1991, N. Engl. J. Med. 325: 1738-1740). The other, termed G.sub.i, effects inhibition of enzyme activity through inhibitory receptors (Id.). The G.sub.s and G.sub.i proteins are members of a superfamily of signal-transducing proteins that mediate numerous transmembrane hormone and sensory processes (Id.).
G proteins share a heterotrimeric structure comprising .alpha., .beta. and .gamma. subunits, each the product of a separate gene (Weinstein et al., 1991, N. Engl. J. Med. 325: 1688-1695). The .beta. and .gamma. subunits are tightly associated with each other, and appear to be structurally interchangeable (Levine, 1991, N. Engl. J. Med. 325: 1738-1740). The .alpha. subunit contains a guanine nucleotide binding site and has intrinsic guanosine triphosphatase ("GTPase") activity (Id.). Functional specificity of G proteins is thought to derive from the identity of their .alpha. subunits, which exhibit the greatest structural diversity, allowing discrimination among multiple receptors and effector molecules (Id.).
Signal transduction begins by the binding of a stimulatory hormone, neurotransmitter, or drug to its receptor(Id.). The activated receptor then interacts with G.sub.s, causing it to release guanosine diphosphate ("GDP") and thereby allow the binding of guanosine triphosphate ("GTP") to its guanine nucleotide binding site (Id.). This binding triggers the dissociation of the .alpha. chain from the hetero-trimer. The released G.sub.s .alpha. protein stimulates adenylyl cyclase activity and thereby increases the synthesis of cAMP, which, in turn, stimulates a physiological response via protein kinase A ("PKA"; Id.). Finally, the bound GTP is hydrolysed to GDP, promoting the reassociation of the .alpha., .beta. and .gamma. subunits, which restores G.sub.s .alpha. to an inactive state (Id.).